NSP7 Molecular Degrader Attenuates Coronaviral Infection Through the β‐TrCP1/FBXO5 Axis

Abstract NSP7 (Non‐Structural Protein 7) of SARS‐CoV‐2 is a crucial component for viral replication and transcription. In this study, it is revealed that the host E3 ubiquitin ligase FBXO5 suppresses viral replication by mediating NSP7 lysine‐48‐linked ubiquitination and subsequent proteasomal degradation. Interestingly, it is also determined that NSP7 expression impairs the host antiviral response by inhibiting the ISGylation of melanoma differentiation‐associated protein 5 (MDA5), a key sensor for viral RNA. Through an unbiased esiRNA screen, it is identified that NSP7 ubiquitination is coregulated by β‐TrCP1 and the kinase TAF1. Additionally, this study uncovers a small molecule FBXO5 stabilizer that disrupts the β‐TrCP1–FBXO5 interaction, thereby markedly enhancing NSP7 degradation and effectively mitigating SARS‐CoV‐2 infection. Taken together, the findings reveal a novel mechanism for NSP7 regulation and suggest that small‐molecule activators of the E3 ubiquitin ligase FBXO5 represent a promising new class of host‐directed antiviral therapies.